1. Field of the Invention
The present invention relates to treatment of traumatic brain injury in mammals. More particularly, the present invention relates to treatment of concussions as mild to moderate to severe traumatic brain injuries. The present invention also relates to treatments using gallium compounds to reduce oxidative stress levels in the brain, after the injury.
2. Description of Related Art Including Information Disclosed Under 37 CFR 1.97 and 37 CFR 1.98.
Traumatic brain injury or concussion is the leading cause of death in people under the age of 45 in the United States. Data from The Center for Disease Control (CDC) indicate that approximately every 22 seconds someone in the United States sustains a serious traumatic brain injury. Traumatic brain injuries can range from mild to moderate to severe. Traumatic brain injury (TBI) and concussion are used interchangeably. There are about 3.8 million sports and recreational related concussions in the United States every year with 1,365,000 emergency room visits and 52,000 deaths.
The current treatment for traumatic brain injury or concussion is docosahexaenoic acid (DHA). Concussion treatment usually consists of only patient rest for days to months to allow for the brain to heal. Docosahexaenoic acid (DHA) has been found to both successfully treat the brain damage of patients after concussion but also to offer protection and prevent neuron damage if taken prior to a concussion in rat studies. See, for example, Bailes, J. E. and Mills, J. D. Docosahexaenoic acid reduces traumatic brain injury in a rodent head injury model. I Neurotrauma. 2010, Sep. 27, 1617-1624; Mills, J. D.; Bailes, J. E.; Sedney, C. L.; Hutchins, H. and Sears, B. Omega-3 fatty acid supplementation and reduction of traumatic axonal injury in a rodent head injury model. I Neurosurg. 2011, January, 114(1), 77-84 and Bailes, U.S. Pat. App. Pub. No. US2011/0086914, Apr. 14, 2011.
The trauma of cerebral concussion generates compressive, tensile, and rotational forces resulting in diffuse axonal injury. Immediately following the injury there is a sudden intracellular efflux of potassium and an influx of calcium ions producing a hypercalcemia condition in the brain. The concussed brain goes into a period of depressed metabolism with continued increases in calcium potentially impairing mitochondrial oxidative metabolism. The calcium accumulation can lead to cell death and disrupt neurofilaments and microtubules. The calcium accumulation is seen within hours of a concussion and persists for two to four days after an event. Additionally, cerebral swelling as a result of calcium and sodium influx occurs post concussion and further exposes the patient to additional risk as secondary injury to the brain. See Giza, C. C. and Hovda, D. A. The Neurometabolic Cascade of Concussion. I Athletic Training. 2001, 36(3), 228-235, which describes the series of events following a concussion, including the associated chemical pathways.
Leading developments in these chemical imbalances focus on the calcium influx. According to National Institute of Neurological Disorders and Stroke (NINDS), “Discussion on Traumatic Brain Injury: Hope through Research”, Apr. 15, 2011, “[o]ne area of research that shows promise is the study of the role of calcium ion influx into the damaged neuron as a cause of cell death and general brain tissue swelling. Calcium enters nerve cells through damaged channels in the axon's membrane. The excess calcium inside the cell causes the axon to swell and also activates chemicals, called proteases, that break down proteins. One family of proteases, the calpains, are especially damaging to nerve cells because they break down proteins that maintain the structure of the axon. Excess calcium within the cell is also destructive to the cell's mitochondria, structures that produce the cell's energy. Mitochondria soak up excess calcium until they swell and stop functioning. If enough mitochondria are damaged, the nerve cell degenerates. Calcium influx has other damaging effects: it activates destructive enzymes, such as caspases that damage the DNA in the cell and trigger programmed cell death, and it damages sodium channels in the cell membrane, allowing sodium ions to flood the cell as well. Sodium influx exacerbates swelling of the cell body and axon. NINDS researchers have shown, in both cell and animal studies that giving specialized chemicals can reduce cell death caused by calcium ion influx.” NIH. www.ninds.nih.gov/disorders/tbi/detail_tbi.htm.
Pain blockers are already known to inhibit the calcium channels, such as neuropathic pain blockers known as N-type voltage-gated calcium channel blockers (N-type VGCC blockers). A recent approach in the treatment of traumatic brain injury is research using N-type VGCC blockers such as SNX-111 (Zirconotide) (Samii et al.) and SNX-185 (Lee et al.; Shahlaie et al.) in studies with rats, which were found to be effective as neuropathic pain blockers and as neuroprotective agents in traumatic brain injury. See, Samii, A.; Badie, H.; Fu, K.; Luther, R. R. and Hovda, D. A. Effects of an N-type calcium channel antagonist (SNX 111; Ziconotide) on calcium-45 accumulation following fluid-percussion injury. I Neurotrauma. 1999, October, 16(10), 879-92; Lee, L. L.; Galo, E.; Lyeth, B. G.; Muizelaar, J. P. and Berman, R. F. Neuroprotection in the rat lateral fluid percussion model of traumatic brain injury by SNX-185, an N-type voltage-gated calcium channel blocker. Exp. Neurol. 2004, November, 190(1), 70-8; and Shahlaie, K.; Lyeth, B. G.; Gurkoff, G. G.; Muizelaar, J. P. and Berman, R. F. Neuroprotective Effects of Selective N-Type VGCC Blockade on Stretch-Injury-Induced Calcium Dynamics in Cortical Neurons. J. Neurotrauma. 2010, January, 27(1), 175-187.
The research on pain blockers with effects on brain injury recovery has been extended to human applications. For example, SNX-111 was recently found to be biologically active as a therapeutic agent in humans for the treatment of neuropathic pain and for neuroprotection after ischemic brain injury. McGuire, D.; Bowersox, S.; Fellmann, J. D. and Luther, R. R. Sympatholysis After Neuron-Specific, N-Type, Voltage-Sensitive Calcium Channel Blockade: First Demonstration of N-Channel Function in Humans. J. Cardiovascular Pharmacology. 1997, September, 30(3), 400-403.
The prior art studies show a reduction of trauma-induced calcium accumulation in the cerebral cortex and especially the hippocampus tissue. This work using N-type VGCC neuropathic pain blockers is encouraging for treating posttraumatic calcium accumulation using other neuropathic pain blockers that limit the calcium levels of traumatic brain injury.
Gallium compounds are also known effective drugs for reducing calcium levels in hypercalcemia patients and treating neuropathic pain, like N-type VGCC blockers. Gallium compounds have been studied for a variety of neurological aliments (Bernstein, U.S. Pat. No. 8,168,214). Gallium compounds are used to inhibit bone calcium loss (hypercalcemia) in cancer patients. See Warrell, R. P.; Brockman, R. S.; Coonley, C. J.; Isaacs, M. and Staszewski, H. Gallium nitrate inhibits calcium resorption from bone and is effective treatment for cancer-related hypercalcemia. I Clinical Investigation. 1984, 73, 1487-1490; and Todd, P. A. and Fitton, A. Gallium nitrate. A review of its pharmacological properties and therapeutic potential in cancer related hypercalcemia. Drugs. 1991, August, 42(2), 261-73 regarding use of gallium nitrate. Also, Bradley, et al., U.S. Pat. No. 5,196,412, describes compounds of gallium (III), which can be given orally to achieve high serum levels of gallium (III) for the treatment of hypercalcemia of malignancy and related disorders of bone metabolism.
Gallium compounds are known to both rapidly reduce edema in animals and humans. For example Gerber et al., U.S. Pat. No. 5,700,487, discloses a method of treating pulmonary inflammation in mammals, comprising administering an effective amount of a pharmaceutically acceptable gallium compound and wherein said gallium is elected from the group consisting of gallium nitrate, gallium citrate, gallium chloride, gallium carbonate, gallium acetate, gallium tartrate, gallium oxalate, gallium oxide, gallium arsenide and hydrated gallium oxide.
Julian, U.S. Pat. No. 7,354,952, discloses novel pharmaceutical gallium compositions, including gallium complexes having increased oral bioavailability relative to uncomplexed gallium salts. Such compositions are useful in the treatment of conditions and diseases in which inhibition of abnormally increased calcium resorption is desired, including cancer, hypercalcemia, osteoporosis, osteopenia and Paget's disease.
Jiang et al., U.S. Pat. No. 7,119,217, incorporated herein by reference, discloses novel tri(alkylcarboxylato) gallium (III) compounds, exemplified by tripalmitato gallium (III), methods for making them, pharmaceutical compositions containing them, and methods of using the pharmaceutical compositions. These compounds may be useful especially since a DHA is a member of this family of compounds.
Gallium compounds are known treatment in humans for cancer and pain. U.S. Pat. No. 4,704,277 shows that doses of 100-300 mg/sq mm m/day of gallium nitrate over 5-7 days reduce calcium excretion by 70+18%. In the cancer treatments, the gallium appears to inhibit calcium resorption from bone and the exact mechanism is unknown although it could be a reaction with the calcium apatite bone structure binding the calcium into a harder bone structure.
Gallium nitrate is a particular gallium compound. Gallium nitrate is known to treat mammals for pain and anti-bacterial agents. Matkovic et al., U.S. Pat. No. 5,175,006 discloses inflammation pain treatment, and Gerber et al., U.S. Pat. No. 5,700,487, describes pulmonary inflammation treatment in humans and animals. Gallium compounds are also powerful antibacterial and anti-pathogenic agents as taught by Schlesinger et al., U.S. Pat. No. 6,203,822, which further discloses the use of gallium-containing compounds to inhibit intracellular pathogens including pathogens that are members of the genus Mycobacteria, Legionella, Histoplasma, and Leishmania and to organisms causing chronic pulmonary infection such P. aeruginosa. Additionally, gallium nitrate has been shown to be an effective for wound treatment as taught by Rogosnitzky, U.S. Pat. App. Pub. No. 20110104246, as a pharmaceutical composition and method for topical wound treatment by topical treatment with gallium salts, preferably gallium nitrate.
Prior art studies have characterized the chemical imbalances that result from after a traumatic brain injury or concussion. Traumatic brain injury is associated with chemical imbalances at the blood brain barrier and in the brain. There are molecular biomarkers of this chemical imbalance, and these biomarkers are oxidatively modified to carbonyl groups, such that oxidative stress levels indicate the presence of these biomarkers. See Mendes Arent, Andre, Luiz Felipe de Souza, Roger Wals, and Alcir Luiz Dafre, “Perspectives on Molecular Biomarkers of Oxidative Stress and Antioxidant Strategies in Traumatic Brain Injury” BioMed Research International, vol. 2014, Article ID 723060, http://dx.doi.org/10.1155/2014/723060. The calcium influx is still present from the injury, but a further indicator of a concussion is increase in oxidative stress levels by an influx of reactive oxygen species (ROS). The reactive oxygen species (ROS) are highly reactive molecules, which damage cellular components. The reactive oxygen species (ROS) are harmful molecules with free radicals to damage DNA, lipids, and proteins, resulting in cell death. ROS is difficult to measure because the short life span. Thus, indirect measurements of ROS by protein carbonyls and protein nitration can indicate levels of oxidative stress. See Abdul-Muneer, P. M., Heather Schuetz, Fang Wang, Maciej Skotak, Joselyn Jones, Santhi Gorantla, Matthew C. Zimmerman, Namas Chandra, and James Haorah “Induction of Oxidative and Nitrosative damage leads to Cerebrovascular Inflammation in Animal Model of Mild Traumatic Brain Injury Induced by Primary Blast”, Free Radical Biol. Med., 2013 July; 60:282-291.
It is an object of the present invention to provide a treatment for traumatic brain injury or concussion.
It is another object of the present invention to provide a treatment for traumatic brain injury or concussion with a gallium compound.
It is still another object of the present invention to provide a treatment for traumatic brain injury with a gallium compound to prevent secondary injury to the brain after the initial injury.
It is still another object of the present invention to provide a treatment for traumatic brain injury to prevent secondary injury to the brain by reducing oxidative stress levels in the brain, after the initial injury.
These and other objects and advantages of the present invention will become apparent from a reading of the attached specification and appended claims.